This invention is in the field of diseases related to vasoconstriction, and in particular to the use of relaxin to treat diseases related to vasoconstriction.
Vasoconstriction, or the reduction in the cross-sectional area of the lumen of small blood vessels, is a potentially lethal condition arising in a variety of pathologies, and is due either to vasospasm, inadequate vasodilation, thickening of the vessel wall, or the accumulation of flow-restricting materials on the internal wall surfaces or within the wall itself. Vasoconstriction is a major factor in various hypertensive vascular diseases, as well as conditions which result from such diseases, including progressive generalized atherogenesis, myocardial infarct, stroke, hypertension, glaucoma, migraine, ischemia, and diabetes mellitus, among others.
Hypertension produced by renal disease is generally the result of either an alteration in the renal handling of sodium and fluids leading to volume expansion or an alteration in renal secretion of vasoactive materials, resulting in a systemic or local change in arteriolar tone. The main subdivisions of renal hypertension are renovascular hypertension, and renal parenchymal hypertension.
Hypertensive vascular disease is currently treated with drugs such as diuretics; antiadrenergic agents; vasodilators; calcium entry blockers; angiotensin-converting enzyme (ACE) inhibitors; angiotensin receptor antagonists; and growth factors.
The extent of ischemic myocardial injury caused by coronary vessel occlusion may be mitigated by the provision of collateral blood flow to the myocardium and the subendocardial layers of the heart. Charney et al. (1993) Am. Heart J. 126:937-945. Currently, therapeutic angiogenesis is designed to promote the development of supplemental collateral vessels as a means of preserving heart function following an ischemic event. Losordo et al. (1998) Circulation 98:2800-2804; Patel et al. (1999) Human Gene Therapy 10:1331-1348; and Henry (1999) British Med. J. 318:1536-1539. Collateral vessel formation and increased blood flow due to new vessel development and vasodilation of both new and pre-existing blood vessels have been shown to preserve certain aspects of heart function. Two agents that have been used in therapeutic angiogenesis in animal models of chronic myocardial ischemia are vascular endothelial cell growth factor (VEGF), which is an angiogenic and vasodilatory growth factor, and the angiogenic protein basic fibroblast growth factor (bFGF). Harada et al. (1994) J. Clin. Invest. 94:623-630; Lopez et al. (1998) Cardiovasc. Res. 40:272-281 and Unger et al. (1994) Am. J. Physiol. 266:H1588-H1595. However, negative consequences, such as hypotension, tachycardia and reduced cardiac output have been observed when VEGF is given to patients. Yang et al. (1998) J. Pharmacol. Exp. Ther. 284:103-110.
To minimize the side effect profile of systemic VEGF and FGF administration, current approaches to induce revascularization and reoxygenation have moved toward direct myocardial or pericardial injection of naked DNA for VEGF, or of VEGF or bFGF protein directly. This requires invasive procedures, often involving thoracotomy. A safe, non-toxic, non-invasive method of promoting angiogenic growth factor expression and a subsequent increase in collateral vessel development could have enormous impact.
Relaxin (RLX) is a low molecular weight protein of approximately 6,000 Da belonging to the insulin-growth factor family that circulates during the luteal phase of the menstrual cycle and throughout gestation in women. It is also produced by the prostate in men. RLX is also a pregnancy hormone in rats. In both species, circulating levels derive from the corpus luteum. Relaxin consists of two peptide chains, referred to as A and B, joined by disulfide bonds with an intra-chain disulfide loop in the A-chain in a manner analogous to that of insulin.
In view of the ongoing problems associated with hypertensive vascular disease, it is clear that there is a need in the art for additional means of treating hypertensive vascular disease. The present invention addresses this need and provides related advantages as well.
The present invention provides methods for treating diseases or disorders related to vasoconstriction, generally comprising administering a formulation comprising a therapeutically effective amount of relaxin. The formulation may be administered by injection, or by sustained-release modes of administration, over a period of time and in amounts which are effective to treat the vasoconstriction-related disease or disorder. Relaxin can act to increase vasodilation, to increase neovascularization (i.e., stimulate, increase, or promote angiogenesis), or both, thereby alleviating the disorder, or symptoms of the disorder. Thus, the invention further provides methods for increasing vasodilation, and methods of stimulating angiogenesis in an individual, generally comprising administering a formulation comprising a pharmaceutically effective amount of pharmaceutically acceptable carrier having therein therapeutically active relaxin.
The invention further provides methods for treating angiotensin-II (AngII)-mediated vasoconstriction. These methods generally comprise administering a formulation comprising an amount of relaxin effective to reverse, inhibit, or reduce the vasoconstricting effects of AngII.
The invention further provides methods for treating endothelin-1 (ET-1)-mediated vasoconstriction. These methods generally comprise administering a formulation comprising an amount of relaxin effective to reverse, inhibit, or reduce the vasoconstricting effects of ET-1. In some embodiments, the methods comprise increasing endothelin type B receptor activation in a cell in a blood vessel by administering relaxin to the individual.
The invention further provides methods for treating an ischemic condition, generally comprising administering a formulation comprising an amount of relaxin effective to stimulate or promote angiogenesis and/or vasodilation, thereby treating the ischemic condition. The methods are useful in treating a variety of ischemic conditions. In some embodiments, methods are provided for treating an ischemic condition which arises as a result of myocardial infarct. In other embodiments, methods are provided for treating an ischemic condition associated with a wound. Thus, the invention further provides methods for promoting wound healing.
The invention further provides methods for stimulating angiogenic and/or vasodilatory cytokine expression generally comprising administering a formulation comprising an amount of relaxin effective to vasodilate blood vessels and/or stimulate or promote angiogenic cytokine production. In some embodiments, the methods provide for stimulating expression of basic fibroblast growth factor (bFGF) and/or vascular endothelial cell growth factor (VEGF). Such methods are useful in treating a wide variety of diseases which can be treated by increasing blood flow at or near the site of disease.
The invention further provides a method of increasing renal vasodilation and hyperfiltration, generally comprising administering a formulation comprising an amount of relaxin. These methods are useful in treating a variety of renal pathologies. Accordingly, the invention further provides methods of treating a renal pathology related to vasoconstriction.
The invention further provides a method of reducing pulmonary hypertension, generally comprising administering a formulation comprising an amount of relaxin.
An advantage of the present invention lies in the fact that the safety profile of relaxin in humans is superior to other agents, such as VEGF and FGF.
A further advantage of the use of relaxin to treat hypertensive vascular diseases is that it is effective in both males and females.
Another object of the invention is a method whereby therapeutically effective amounts of relaxin are repeatedly administered to a patient over a period of time to obtain a beneficial therapeutic result.
Another aspect of the invention is to repeatedly or substantially continuously administer relaxin over a period of time in a manner so as to maintain therapeutic blood levels of relaxin over periods sufficient to obtain therapeutic results.
A feature of the invention is injectable and sustained-release formulations of relaxin which are useful in the method of the invention wherein the formulation comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of relaxin.
These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the invention as more fully described below.